Although the immune response is often perceived as beneficial, in certain circumstances the immune response to an antigen can actually be harmful to the animal in which the immune response occurs. Examples of situations where the immune response creates conditions where the animal is subject to serious pathologic sequelae are in such areas as graft versus host (GVH) rejection and host versus graft (HVG) rejection, and certain autoimmune diseases, such as lupus erythematosus, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, and rheumatoid arthritis.
The utilization of organs from nonhuman donors is an appealing solution to the increasing shortage of organs available for clinical transplantation. Although xenotransplantation from primate donors has been performed with limited success clinically, the use of distantly related species, such as the pig, avoids ethical dilemmas, potential virus transmission, and limited availability associated with the use of primates as xenograft (Xg) donors. However, the use of organs from distantly related species for xenotransplantation has been hampered by the occurrence of hyperacute rejection (HAR), a process that leads to irreversible Xg damage and loss within minutes to hours of transplantation. HAR is thought to be mediated by the binding of naturally occurring xenoreactive antibodies to the endothelium of the Xg, in particular, donor vascular endothelial cells, with subsequent activation of the classical pathway of complement (C). It has been shown that a predominate specificity of these antibodies is to the oligosaccharide moiety galactose(.alpha.1-3)galactose for primate recipients. Alternative C pathway activation also contributes to HAR in some species combinations. The complement cascade is activated following the binding of xenoreactive antibodies to donor tissue. This cascade leads to endothelial activation, thrombosis, intravascular coagulation, edema, and eventually loss of function of the transplanted organ. However, if xenoreactive natural antibodies are eliminated, the presence of complements is still adequate to mediate a rejection event, presumably via the alternative pathway.
Complement-mediated cell lysis also plays a role in allograft rejection, and has therefore presented a hurdle in methods of allograft transplantation. Thus, complement-mediated tissue deterioration can cause dysfunction of donor organs and tissues both from human and non-human sources. In addition, complement activation causes the deterioration of blood products, such as platelets. Thus, the length of time that blood can be stored (e.g., for transfusions) is diminished by the activity of complement.
Humans and microorganisms express complement inhibitors (CIs), which serve to inhibit complement-mediated attacks. CIs contain short consensus repeats (SCRs), which are 60-70 amino acid-long regions. The number of SCRs varies among CIs. For example, the human CI Complement Receptor 1 (CR1) has 30 SCRs, while the human CI Decay Accelerating Factor (DAF) has 4 SCRs. The binding specificity of the various CIs for the various complement factors also varies. For example, Complement Receptor 1 (CR1) in humans binds C3b, C3bi, and C4b, and functions via two mechanisms: Factor I cofactor activity and convertase decay acceleration. Another human CI, Decay Accelerating Factor (DAF) binds C3b and C4b, but only has convertase decay accelerating activity. Membrane Cofactor Protein (MCP), a different human CI binds C3b and C4b,but only has Factor I cofactor activity.